Abstract
Protein kinase C iota (PKCɩ) is a novel protein containing 596 amino acids and is also a member of atypical kinase family. The role of PKCɩ has been explored in neurodegenerative diseases, neuroblastoma, ovarian and pancreatic cancers. Single nucleotide polymorphisms (SNPs) have not been studied in PKCɩ till date. The purpose of the current study is to scrutinize the deleterious missense variants in PKCɩ and determine the effect of these variants on stability and dynamics of the protein. The structure of protein PKCɩ was predicted for the first time and post translational modifications were determined. Genetic variants of PKCɩ were retrieved from ENSEMBL and only missense variants were further analyzed because of its linkage with diseases. The pathogenicity of missense variants, effect on structure and function of protein, association with cancer and conservancy of the protein residues were determined through computational approaches. It is observed that C1 and the pseudo substrate region has the highest number of pathogenic SNPs. Variations in the kinase domain of the protein are predicted to alter overall phosphorylation of the protein. Molecular dynamic simulations predicted noteworthy change in structural and functional dynamics of the protein because of these variants. The study revealed that nine deleterious variants can possibly contribute to malfunctioning of the protein and can be associated with diseases. This can be useful in diagnostics and developing therapeutics for diseases related to these polymorphisms.
Highlights
PKC iota that has a significant role in the progression of cell cycle, its inhibition can lead to the obstruction of cell cycle progression
The protein is found to have 596 amino acids with four important domains: PB1 domain, C1 domain (Pseudo substrate domain), protein kinase domain containing the active site of the protein and AGC kinase domain
Protein kinase domain of PKCι was aligned with crystal structure of kinase domain (38AX:ID from protein data base)
Summary
PKCɩ is a member of a serine threonine kinase family that plays an important role in the phosphorylation of hydroxyl group in protein residues (serine and threonine). Atypical isoforms (PKCɩ and PKCζ) are different from the other PKC family members because of the distinct structural and functional characters They do not need Ca2+ and diacylglycerol for the functional activation[1]. PKCɩ is directly linked to oncogenic Ras signaling It plays a significant role in Ras mediated transformation in intestinal epithelium that leads to malignancy in r ats[4]. To use various bioinformatics tools on the predicted 3D structure of the protein to understand the possible impact of these variants on the structure and function of the protein, prediction of post translational modification of PKCι along with its involvement with cancer and survival This is a first comprehensive in silico analysis of missense variants of this protein. The outcomes might be useful in designing precision medicines for associated diseases
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